Chemokines are a large family of low molecular weight, inducible, secreted, proinflammitory cytokines which are produced by various cell types. They have been divided into several subfamilies on the basis of the positions of their conserved cysteines. The CXC family includes interleukin-8 (IL-8), growth regulatory gene, neutrophil-activating peptide-2, and platelet factor 4 (PF-4). Although IL-8 and PF-4 are both polymorphonuclear chemoattractants, angiogenesis is stimulated by IL-8 and inhibited by PF-4. The CC family includes monocyte chemoattractant protein-1 (MCP-1), RANTES (regulated on activation, normal T cell-expressed and secreted), macrophage inflammatory proteins (MIP-1.alpha., MIP-1.beta.), and eotaxin. MCP-1 is secreted by numerous cell types including endothelial, epithelial, and hematopoietic cells, and is a chemoattractant for monocytes and CD45RO+lymphocytes (Proost, P. (1996)Int J. Clin. Lab. Res. 26: 211-223; Raport, C. J. (1996) J. Biol. Chem. 271: 17161-17166).
Cells respond to chemokines through G-protein-coupled receptors. These receptors are seven transmembrane molecules which transduce their signal through heterotrimeric GTP-binding proteins. Stimulation of the GTP-binding protein complex by activated receptor leads to the exchange of guanosine diphosphate for guanosine triphosphate and regulates the activity of effector molecules. There are distinct classes of each of the subunits which differ in activity and specificity and can elicit inhibitory or stimulatory responses. When stimulation of the known cytokine receptors shows agonist-dependent inhibition of adenylyl cyclase and mobilization of intracellular calcium, the receptor coupling to G.sub..alpha. i subunits (Myers, S. J. et al (1995) J. Biol. Chem. 270: 5786-5792).
Chemokine receptors play a major role in the mobilization and activation of cells of the immune system. The effects of receptor stimulation are dependent on the cell type and include chemotaxis, proliferation, differentiation, and production of cytokines. Chemokine stimulation produces changes in vascular endothelium, chemotaxis to sites of inflammation, and activates the effector functions of cells (Taub, D. D. (1996) Cytokine Growth Factor Rev. 7: 355-376).
The chemokine receptors display a range of sequence diversity and ligand promiscuity. The known chemokine receptor protein sequence identities range from 22 to 40%, and certain receptors can respond to multiple ligands. Although mainly expressed in immune cells, viral homologues are expressed by human cytomegalovirus and Herpesvirus saimiri. The chemokine receptor known as the Duffy blood group antigen binds both CC and CXC family chemokines and serves as the receptor on erythrocytes for the malarial parasite Plasmodium vivax. Members of the chemokine receptor family are used as co-receptors with CD4 for HIV-1 entry into target cells. Several receptors have recently been cloned. The human chemokine receptor, R12, was isolated by cross-hybridization of an APJ/R20 probe on a human genomic library. R12 is most similar to the R20 orphan receptor (which has homology with the angiotensin receptor) and shows between 22 and 26% homology to characterized chemokine receptors including IL-8A and B, and MCP-1.alpha. and 1.beta.. (Murphy, P. M. (1994) Annu. Rev. Immunol. 12:593-633; Raport, C. J. et al (1996) J. Leuk. Biol. 59: 18-23; He, J. et al (1997)Nature 385: 645-649).
The discovery of proteins related to human chemokine receptor R12 and the polynucleotides encoding them satisfies a need in the art by providing new compositions useful in diagnosis and treatment of disorders associated with inflammation and viral infection.